This R21 application responds to PA-07-227, which describes an urgent need for a greater understanding of the underlying neurobiological and behavioral mechanisms in the addictive effects of methamphetamine (MA) and cocaine. The use and abuse of MA and cocaine is a major public health concern world-wide;despite significant effort to identify indirectly and directly acting dopamine (DA)-based candidate medications as potential agonist-based treatments, no effective pharmacotherapies are yet available for the management of addiction to MA and cocaine. As non-dopaminergic mechanisms, including nicotinic systems, also may contribute importantly to the addictive effects of these psychomotor stimulant drugs, the study of non- dopaminergic ligands, including nicotinic drugs, may lead to novel 'agonist-based'candidate medications. Based on reports in the scientific literature and our own preliminary results, nicotinic agonists can interfere with the expression of behavioral and neurochemical effects of MA, and therefore, may be suitable 'agonist-based'candidate medications for stimulant abuse and addiction. To evaluate this medication strategy, we propose to determine whether the prototypic agonist nicotine (NIC) attenuates the abuse-related behavioral and neurochemical effects of MA in a primate species. Using established methods to study the discriminative- stimulus and observable effects of dopaminergic drugs, we plan to directly analyze how acute or chronic (15- day) treatment with nicotine may alter behavioral effects of MA. Drug discrimination studies will be conducted in monkeys prepared with dialysis cannulae targeting either the striatum or prefrontal cortex. During drug testing, dialysate samples will be removed and analyzed for DA level. These coordinated studies will allow a comprehensive assessment within the same test session of how the behavioral and neurochemical effects of MA may be modified by nicotinic agonist treatment. The results of these studies will provide important information regarding the potential therapeutic value of nicotinic-based medication strategies for the management of abuse and addiction to MA and related stimulants. The proposed research also should lead to further studies to identify novel nicotinic targets to help combat MA addiction. PUBLIC HEALTH RELEVANCE: Methamphetamine abuse and addiction has emerged as a major public health concern, and effective treatments with which to help manage this problem have not yet been identified. This project is designed to study the potential therapeutic value of nicotinic-based medication strategies. The proposed research will lead to a greater understanding of the mechanisms responsible for methamphetamine addiction and may identify novel nicotinic targets to help combat methamphetamine addiction.